Pokemon HeartGold and SoulSilver contain the League Champions of every region represented thus far in the series: Blue and Red of Kanto, Lance of Pokemon Gold/Silver, Steven Stone of Pokemon Ruby/Sapphire, and Cynthia of Pokemon Diamond/Pearl/Platinum. Only Wallace of Pokemon Emerald - the expansion version of Ruby/Sapphire - is left unseen.

In Pokemon HeartGold and SoulSilver, a special "MICHINA" Arceus was distributed at Toys R Us stores. This Arceus was first interesting as it knew three moves it normally never can learn: Roar of Time, Spacial Rend, and Shadow Force, which are interestingly the signature moves of Dialga, Palkia, and Giratina, respectively, the three dimension-governing Pokemon Arceus was claimed in Sinnoh-region lore to have created after the universe so as to govern it. The Arceus would be able to take you to the Sinjoh Ruins, "Sinjoh" being an amalgamation of the words "Sinnoh" and "Johto" (since Arceus originally was Sinnoh-native, and HG/SS take place in Johto): there, you can find three Eggs and take one, which will hatch into a Level 1 Dialga, Palkia, or Giratina.

Pokemon HeartGold and SoulSilver are the first games that show the influence of Nature on a Pokemon's stats: in their Summary screen, if the stat is lowered 10% by Nature the stat's name is blue, and red if it is raised by 10%. This later became tradition for the series.

Pokemon HeartGold and SoulSilver are notably the remakes of the GBC Pokemon Gold and Silver games. Obviously, this comes with a number of changes, although much of the formula remains the same. However, Game Freak did make one special change to this: your Pokemon can now follow you in the field. This is much akin to the style of Pokemon Yellow in which your Pikachu will be able to follow you around: in fact, Pokemon Yellow (not even G/S/C) is the only prior incidence of this!